Cancer-host interactions play an important role in cancer development. We identified ATF3, an adaptive-response gene, in the host to facilitate metastasis. We also demonstrated that the macrophage is one of the key cell types for host-ATF3 to function. Furthermore, matrix metalloproteases 9 is a functionally important target gene of ATF3 in co-culture assays. Gene profiling with bioinformatics analyses indicated that ATF3 downstream gene-signatures derived from tumor-associated macrophages in a mouse model can distinguish human tumor stroma from “distant” stroma in and can stratify the patients into high- versus low-risk groups. Importantly, multivariate analyses indicated that high expression of ATF3 itself in mononuclear cells within breast tumors is an independent predictor for breast cancer-specific death in a cohort of patients. Approximately 21 days after orthotopic injection of PyMT breast cancer cells into syngeneic C57BL/6 mice (WT or ATF3 KO hosts) tumors were removed (tumors were ~1 cm cubic in volume), enzymatically digested to generate single cell suspensions, stained, and sorted for F4/80 and CD45 double positive cells by FACS. Isolated cells were lysed in TRIzol, processed to generate total RNA, and gene expression analyzed by microarray. Four replicate WT TAM samples and four replicate ATF3 KO TAM samples were analyzed.